The OBR Blog

Some 30,000 professionals from around the world will attend the 2016 ASCO Annual Meeting in Chicago, IL. The theme of the meeting is Collective Wisdom: The Future of Patient-Centered Care and Research.

Five studies selected from the 5,200 abstracts submitted to ASCO were featured at a pre-meeting press cast. The topics covered by these abstracts included the:

Impact of tumor site on treatment for metastatic colorectal cancer

Long-term follow-up of immunotherapy for melanoma

Precision medicine based on grouping patients according to biomarkers rather than tumor type

A retrospective analysis of the phase 3 CALGB/SWOG 80405 (Alliance trial) showed that colorectal cancer tumors arising in the right side of the colon (cecum and ascending colon) behave differently than those that arise from the left side (the descending colon, sigmoid colon, and rectum).

These differences have treatment implications.

Patients whose primary tumors that arise on the left side have significantly improved survival compared with right-sided primary tumors (the cecum and ascending colon): median overall survival (OS) was 33.3 months vs 19.4 months, respectively. This analysis was based on tumors with wild-type KRAS.

“While previous studies had suggested that tumor location may impact colorectal cancer outcomes, the effect we observed in this analysis appears to be far greater than we expected. These findings will likely change the way we approach colorectal cancer treatment and research, even as we seek to understand the biology driving the differences in outcomes between right- and left-sided tumors,” said lead author Alan Venook, MD, University of California, San Francisco.

An exploratory analysis suggested that OS and PFS were prolonged with cetuximab and with bevacizumab in left-sided tumors. For patients treated with cetuximab, median OS was 36 months for left-sided tumors vs 16.7 months for right-sided tumors; for those who received bevacizumab, median OS was 31.4 months and 24.2 months, respectively.

“These data suggest that right-sided tumors get no benefit from cetuximab. Colorectal cancer on the right side of the colon should be treated differently those on the left side. The data suggest that bevacizumab should be included in first-line treatment for metastatic colorectal cancer patients with right-sided primary tumors regardless of KRAS status,” said Dr. Venook.

Pembrolizumab in Advanced Melanoma

Pembrolizumab achieved encouraging survival in patients with advanced melanoma who were pretreated with ipilimumab as well as those who were not, according to results of the phase 1b KEYNOTE-001 trial.

At 36 months, 40% of patients treated with pembrolizumab were alive.

Three different schedules of pembrolizumab were used in the study:

24-month OS ranged from 49% to 52%

36-month OS ranged from 38% to 43%

Best results were observed with pembrolizumab 10 mg/kg every 2 weeks, which was deemed the optimal dose by the investigators

Ninety-one study patients (15%) experienced complete remissions (CR), according to immune-response criteria, and of these, 97% are still in remission. Of these, 61 (64%) went off treatment after a median duration of 23.4 months; only 2 have had disease progression. One of the 2 has been re-started on pembrolizumab, but it is too early to evaluate response.

Median OS was 24.4 months, which is double that for advanced melanoma prior to the introduction of ipilimumab.

“Advanced melanoma is still a very challenging cancer, which it is why it is so remarkable that such a large proportion of patients see a long-term benefit from this therapy. These data confirm the use of pembrolizumab as one of the new standards of care in patients with advanced melanoma regardless of prior treatment,” stated Caroline Robert, MD, PhD, Head of the Dermatology Unit at the Institut Gustave-Roussy, Paris, France.

“These data are incredibly exciting and are the longest follow-up of an anti-PD-1 agent,” said Don Dizon, MD, ASCO spokesperson. “We see response and durable response, and this could represent a potential cure.”

Biomarker-Based Selection of Patients

A meta-analysis that included 346 phase 1 published trials of single agents involving more than 13,000 patients compared studies that used a biomarker-based selection strategy versus those that did not. The studies were published between 2011 and 2013.

A personalized strategy was an independent predictor of improved RR and PFS. In a sub-analysis within targeted arms of these trials, studies that were not guided by biomarker-driven selection criteria had negligible RR.

A sub-analysis of 57 trials of therapies targeted to specific genes or proteins showed that treatment arms based on biomarker selection had tumor shrinkage rates of 31.1% compared with 5.1% for those that did not.

Lead author Maria Clemence Schwaederle, PharmD, Center for Personalized Cancer Therapy and Division of Hematology, University of California, San Diego, said: “Our study suggests that with a precision medicine approach, we can use a patient’s individual tumor biomarkers to determine whether that patient is likely to benefit from a particular therapy, even when therapy is at the earliest stage of clinical development.”

“Targeted therapies by themselves are not effective. They need to be given to the right patient,” she noted. “These were highly refractory patients,” she added.

Results suggest that phase 1 studies, which usually focus on safety, can provide important insights into optimal treatment selection. The author suggested incorporating survival endpoints into phase 1 trials.

“This is a large dataset of more than 13,000 patients. It shows the importance of precision medicine, and that using the genomic and protein biomarkers from the patient’s own tumors improves outcomes compared to approaches used in the past,” said Dr. Dizon.

Family Caregiver Outcomes

Patient-reported outcomes in clinical trials have received increased attention over the past few years. A new study looked at outcomes among family caregivers (FC) of patients with incurable lung and gastrointestinal cancers.

The study found that early integration of palliative care along with oncology care improved depression and aspects of quality of life in FC, including vitality and social functioning.

The study enrolled 350 patients and 275 potentially eligible FC: 137 patients were randomized to an intervention that included at least monthly patient visits with integrated palliative care (FC were not required to attend these visits, although 50% did) and 138 in the control group.

“This work demonstrates that the benefits of early, integrated palliative care models in oncology care extend beyond patient outcomes and positively impact the experience of family caregivers,” said lead author Areej El-Jawahri, MD, Massachusetts General Hospital, Boston, MA.

“Incorporating early palliative care creates a powerful feedback loop in families facing cancer and may make it easier for caregivers to care for their loved ones.”

Transplant for Multiple Myeloma in Era of Modern Therapy

The availability of potent novel therapies for multiple myeloma raises the question of whether autologous stem cell transplant (ASCT) should remain the standard of care for upfront treatment in patients younger than age 65.

An international, multicenter, randomized phase 3 study looked at this question by comparing ASCT versus chemotherapy using novel agents, and found that ASCT should still be considered standard of care for younger newly diagnosed patients.

The first stage of the study compared 4 cycles of bortezomib-melphalan-prednisone (VMP) versus high-dose melphalan (HDM) and single or double ASCT as intensification therapy following induction therapy with bortezomib-cyclophosphamide-dexamethasone and subsequent collection of peripheral blood stem cells.

Results of the first prespecified interim analysis included 1,266 patients who were randomized in a 1:1 ratio to VMP or HDM plus single or tandem ASCT. At 24 months, superior PFS was reported in those randomized to the transplant arm (P=.010), with a benefit across all prespecified subgroups, including high-risk cytogenetics.

A second stage randomized patients in both groups to consolidation therapy with bortezomib/lenalidomid/dexamethasone or no consolidation therapy. Analysis of this stage was not reported at the press cast.

Among patients who had not yet experienced disease progression, those randomized to ASCT had a 24% lower risk of disease progression at any future time point compared with those who did not receive transplant.

In patients with advanced disease, ASCT conferred a 48% lower likelihood of disease progression compared with the VMP group, and those with high-risk cytogenetics, ASCT was associated with a 28% lower risk of progression at any future time compared with the group that did not have transplant.

Additionally, higher rates of very good partial response (VGPR) were observed with the transplant arm: 84% versus 74% for VMP (P<.0001). A Cox regression analysis found that randomization to HDM plus ASCT was an independent predictor of prolonged PFS. Overall survival data are not yet mature, with no apparent difference between the two treatment arms.

“This study shows the superiority of upfront ASCT versus chemotherapy alone in newly diagnosed fit patients. This is further supported by the significant improvement in the rate of VGPR or higher quality response.

“Upfront ASCT still remains the preferred treatment for younger newly diagnosed multiple myeloma patients, even in the novel agent era. Further follow-up of the study is needed,” said lead author Michele Cavo, MD, Head of the Seragnoli Institute of Hematology at the University of Bologna, Italy.

With the annual meeting of the American Society of Clinical Oncology (ASCO) quickly approaching (June 3-7, Chicago), the 2016 event is sure to live up to its reputation for delivering market-changing data and trends from the world of oncology. Below, Kantar Health spotlights four potentially noteworthy abstracts that are likely to generate much discussion and significantly influence patient care. For a complete assemblage of all nine of Kantar Health’s top abstracts of interest, please see the associated article in the May issue of OBR Green.

Management of acute myeloid leukemia (AML) has been largely unchanged over several decades, with first-line induction therapy typically consisting of a combination regimen of cytarabine plus an anthracycline (7+3 most commonly).1 This is a very intensive regimen, and while it is effective at inducing remissions in a high proportion of patients, several subsets of AML patients exist with unmet needs. In patients with high-risk AML, which includes cytogenetic abnormalities as well as those with secondary AML (including those who progressed from myelodysplastic syndrome (MDS)), prognosis is poor. These patients have been the target of recent clinical development in AML. At ASCO 2016 we will see the pivotal results for a novel chemotherapeutic, Vyxeos™ (CPX-351, Celator Pharmaceuticals), which could transform care for a subset of patients. Vyxeos is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio that was designed to maintain an optimized ratio of the two drugs together to maximize efficacy outcomes.

Celator chose to study Vyxeos in the first-line setting in a subpopulation of patients at higher unmet need, specifically those with secondary AML and/or poor cytogenetics. In this patient population, a Phase III trial (NCT01696084) compared Vyxeos versus 7+3 as first induction therapy. In March 2016, Celator announced that this trial had met the primary endpoint of prolonging overall survival (OS), with a 3.6-month improvement favoring the Vyxeos arm (9.6 months vs. 6.0 months, HR 0.69, p=0.005), and landmark analysis suggested the benefit with Vyxeos was maintained over time. Based on these data, Celator plans to file for regulatory approval in the U.S. and Europe in the third quarter of 2016 and first quarter of 2017, respectively. Abstract 7000, Saturday, June 4, 3:00 p.m.

Immunotherapy in head and neck cancer

What discussion of exciting trends would be complete without examination of the PD-1 inhibitors Opdivo™ (nivolumab, Bristol-Myers Squibb/ONO) and Keytruda® (pembrolizumab, Merck)? Since first being approved by the FDA in 2014, these compounds have begun to dominate the market and have been in fierce competition with each other at every step of the way.

In a Clinical Science Symposium titled “Harnessing the Immune System in Head and Neck Cancer: Evolving Standards in Metastatic Disease” (Monday 11:30 a.m. – 1:00 p.m.), a series of abstracts will examine the role of these and similar compounds in patients with squamous cell carcinoma of the head and neck (SCCHN).

First up is Opdivo with updated/reprised data from the Phase III CheckMate 141 trial that compared Opdivo versus investigator’s choice of therapy in patients with SCCHN with tumor progression on or within six months of platinum therapy. Results from this trial showed a significant OS benefit favoring Opdivo (7.5 months vs. 5.1 months, HR 0.70, p=0.0101), which ultimately led to the FDA awarding it Breakthrough Therapy designation in April 2016. These results were presented initially at the 2016 annual meeting of the American Association for Cancer Research (AACR),2 but this reprisal at ASCO will bring the data into view for a much wider audience of clinicians.

Keytruda will follow with a series of abstracts anchored around the first presentation of results from the single-arm KEYNOTE-055 trial that examine efficacy of Keytruda after platinum and Erbitux® (cetuximab, Lilly/Merck KGaA) failure. Results of this study haven’t been reported, but Merck has already filed for approval and the FDA took quick action, setting a priority review PDUFA date of August 9, 2016, by which to act on the application. In the Phase I KEYNOTE-012 study, single-agent Keytruda produced a response rate of 24.8% in a largely third-line or later population,3 and an update on this trial will be reported in this same session at ASCO 2016. Kantar Health will be watching to see whether this level of efficacy can be maintained in the KEYNOTE-055 trial. Also of importance is information on the potential role of the PD-L1 biomarker as a predictor of response to Keytruda in recurrent/metastatic SCCHN, which will be discussed in a third presentation in this session. Biomarkers are a possible point of distinction between the two compounds. Abstracts 6009-6012, Monday, June 6, 11:30 a.m.

Darzalex™ (daratumumab, Genmab/Janssen) was recently approved as a first-in-class anti-CD38 monoclonal antibody in fourth-line multiple myeloma. This approval was based on the results of the pivotal Phase II SIRIUS study, in which single-agent Darzalex resulted in an objective response rate (ORR) of 29.2% in patients who had received a median of five prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.4 Although the SIRIUS trial offered an important opportunity to gain accelerated approval for Darzalex, the true opportunity lies in earlier lines of therapy. As such, Janssen initiated two Phase III studies of Darzalex in combination with the standard of care in second-line myeloma. The first of these studies to report is CASTOR, which compares the combination of Darzalex, Velcade® (bortezomib, Millennium/Janssen) and dexamethasone (VelDex) versus VelDex in patients previously treated with at least one prior line of therapy. In March 2016, Genmab announced that the trial met the primary endpoint of improving progression-free survival (PFS) in an interim analysis (p≤0.0001), prompting the independent data monitoring committee to recommend early stoppage of the trial.

Although it is highly treatable, multiple myeloma is rarely curable, and patients often become resistant to therapy. As such, data from this trial would be very well received if the combination provides a meaningful improvement in time to relapse or minimizes resistance. Darzalex itself is still very new to the market, and as the first human anti-CD38 monoclonal antibody it has the potential to change the landscape. In the second-line setting, Darzalex will be competing directly with Empliciti™ (elotuzumab, AbbVie/Bristol-Myers Squibb) and Kyprolis® (carfilzomib, Amgen), both of which were approved in the past year as part of triplet regimens (both in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone, RevDex). Both regimens produced very strong PFS benefits in comparison with doublet therapy (RevDex). Key for Darzalex will be demonstrating a level of PFS benefit that is at least comparable to that observed with the Empliciti or Kyprolis triplets, and/or other safety or efficacy differentiators, to overcome the fact that it will be third to market in this setting. Abstract LBA4, Sunday, June 5, 3:10 p.m.

In the treatment of HER2+ breast cancer, Genentech/Roche compounds have become the standards of care in most treatment settings – Herceptin® (trastuzumab) in the adjuvant setting, the combination of Herceptin plus Perjeta® (pertuzumab) in first-line metastatic disease, and Kadcyla® (ado-trastuzumab emtansine) in second-line metastatic disease.1 Most recently, Perjeta became part of the first regimen to be FDA-approved for use in the neoadjuvant setting based on a significant improvement in pathologic complete response rate (pCR) for the combination of Perjeta + Herceptin + docetaxel. Roche also has been seeking to advance the development of Kadcyla beyond the relapsed/refractory setting, with several Phase III trials initiated in various settings. The highly anticipated MARIANNE trial was somewhat of a shocking disappointment in December 2014 when it failed to show a benefit for the use of Kadcyla + Perjeta in first-line metastatic disease.5 Similar studies continue in early-stage disease and initial results from the first of these trials, KRISTINE, will be reported at ASCO 2016. KRISTINE (NCT02131064) evaluates the efficacy of Kadcyla + Perjeta in comparison with Herceptin + Perjeta + chemotherapy in the peri-operative setting, with patients receiving six cycles of neoadjuvant (pre-operative) treatment followed by surgery; following surgery, patients will receive adjuvant Kadcyla + Perjeta versus Herceptin + Perjeta.

Results of this study have not been announced publicly, so it’s unknown whether the presentation at ASCO will be positive or negative. The MARIANNE trial in first-line metastatic disease showed no difference in PFS, OS or ORR among the three study arms. However, a Phase Ib/IIa open label study evaluated Kadcyla and docetaxel with or without the addition of Perjeta as neoadjuvant therapy in 70 previously untreated HER2+ locally advanced breast cancer patients (NCT00934856). The pCR rate was relatively similar in patients who received the Perjeta/Kadcyla/docetaxel regimen (60.6%) compared with those who received Kadcyla/docetaxel (56.8%).6 Although the pCR rates in these two arms were similar, both are notably higher than the pCR rate upon which Perjeta + Herceptin + docetaxel was FDA-approved in the neoadjuvant setting (39%).7 Importantly, the Kadcyla + Perjeta combination demonstrated improved safety and quality of life in the MARIANNE trial. The tolerability of this combination will be a key to watch in the KRISTINE trial, as safety takes on even greater importance in potentially curative early-stage disease. Additionally, the KRISTINE trial will be important to watch in terms of potential for short-term advancement of Kadcyla, as well as possible foreshadowing of results to come from the adjuvant KATHERINE and KAITLIN trials. Abstract500, Monday, June 6, 1:15 p.m.